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Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance

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Department of Medicine and Surgery, Bioscience and Medical Embryology Division, University of Perugia, L. Severi Square, 06129 Perugia, Italy
2
Section of Anatomic Pathology and Histology, Department of Medicine and Surgery, University of Perugia, L. Severi Square, 06129 Perugia, Italy
*
Author to whom correspondence should be addressed.
Cancers 2021, 13(12), 2965; https://doi.org/10.3390/cancers13122965
Received: 25 May 2021 / Revised: 9 June 2021 / Accepted: 10 June 2021 / Published: 13 June 2021
(This article belongs to the Section Molecular Cancer Biology)
Metastatic prostate cancer (mPCa) is a well-known lethal condition. One of the mechanisms through which PCa cells become so aggressive is the avoidance of immune surveillance that further fosters cell growth, invasion, and migration. PD-L1/PD-1 axis plays a crucial role in inhibiting cytotoxic T cells and maintaining an immunosuppressive cancer microenvironment. Hence, targeting PD-L1/PD-1 axis represents a potential way to control mPCa. Unfortunately, mPCa patients do not respond to PD-L1/PD-1 axis blockade, focusing the research to understand the possible underpinning mechanisms. Our results provide a novel pathway taking part in cancer immunosurveillance escape and in the above-mentioned immunotherapy resistance, which provides the basis for additional studies aimed at developing novel therapeutic opportunities, possibly also in combination with antibodies blocking PD-L1/PD-1 axis.
Metastatic prostate cancer (mPCa) is a disease for which to date there is not curative therapy. Even the recent and attractive immunotherapeutic approaches targeting PD-L1, an immune checkpoint protein which helps cancer cells to escape from immunosurveillance, have proved ineffective. A better understanding of the molecular mechanisms contributing to keep an immunosuppressive microenvironment associated with tumor progression and refractoriness to PD-L1 inhibitors is urgently needed. In the present study, by using gene silencing and specific activators or scavengers, we demonstrated, in mPCa cell models, that methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs), especially 5-hydro-5-methylimidazolone (MG-H1), and its metabolizing enzyme, glyoxalase 1 (Glo1), contribute to maintain an immunosuppressive microenvironment through MG-H1-mediated PD-L1 up-regulation and to promote cancer progression. Moreover, our findings suggest that this novel mechanism might be responsible, at least in part, of mPCa resistance to PD-L1 inhibitors, such as atezolizumab, and that targeting it may sensitize cells to this PD-L1 inhibitor. These findings provide novel insights into the mechanisms of mPCa immunosurveillance escape and help in providing the basis to foster in vivo research toward novel therapeutic strategies for immunotherapy of mPCa. View Full-Text
Keywords: glyoxalase 1; methylglyoxal; MG-H1; metastatic prostate cancer; PD-L1/PD-1; immune check-point; immunosurveillance; atezolizumab glyoxalase 1; methylglyoxal; MG-H1; metastatic prostate cancer; PD-L1/PD-1; immune check-point; immunosurveillance; atezolizumab
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MDPI and ACS Style

Antognelli, C.; Mandarano, M.; Prosperi, E.; Sidoni, A.; Talesa, V.N. Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance. Cancers 2021, 13, 2965. https://doi.org/10.3390/cancers13122965

AMA Style

Antognelli C, Mandarano M, Prosperi E, Sidoni A, Talesa VN. Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance. Cancers. 2021; 13(12):2965. https://doi.org/10.3390/cancers13122965

Chicago/Turabian Style

Antognelli, Cinzia, Martina Mandarano, Enrico Prosperi, Angelo Sidoni, and Vincenzo N. Talesa 2021. "Glyoxalase-1-Dependent Methylglyoxal Depletion Sustains PD-L1 Expression in Metastatic Prostate Cancer Cells: A Novel Mechanism in Cancer Immunosurveillance Escape and a Potential Novel Target to Overcome PD-L1 Blockade Resistance" Cancers 13, no. 12: 2965. https://doi.org/10.3390/cancers13122965

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